Blood coagulation is a process consisting of a complex interaction of various blood components (or factors) that eventually gives rise to a fibrin clot. Generally, the blood components, which participate in what has been referred to as the coagulation “cascade”, are enzymatically inactive proteins (proenzymes or zymogens) that are converted to proteolytic enzymes by the action of an activator (which itself is an activated clotting factor). Coagulation factors that have undergone such a conversion are generally referred to as “active factors”, and are designated by the addition of the letter “a” to the name of the coagulation factor (e.g. Factor VII(a)).
For patients with severe hemophilia, there is a trend away from on-demand treatment towards prophylactic regimens to prevent bleeding and subsequent joint damage. However, with their short circulating half-life, coagulation factors such as FVIII, FIX and FVIIa in particular, are not ideal for long term prophylactic treatment, as both high doses and frequent injections are required for maintaining pharmacological relevant plasma levels. Current focus is therefore directed towards development of long acting analogues that are better suited for prophylactic use.
Pegylation is an established method for prolonging the circulating half-life of proteins. However, due to the large interaction interface of coagulation factors within the cell membrane, other coagulation factors and co factors there are limited possibilities for chemical modification without a detrimental loss of activity.
There is thus a great need for providing blood coagulation factors with increased plasma half-lives for the prophylactic treatment of hemophilia.
WO 2005/027978 (Novo Nordisk A/S) describes derivatives of glucagon-like-peptide-1 (GLP-1) which have a protracted profile of action wherein said polypeptides are linked to an albumin binding residue via a hydrophilic spacer.
The invention therefore provides novel protein conjugates with improved pharmacological properties as well as methods for their production.